Ribozyme gene therapy for autosomal dominant retinal disease.

Gene delivery to cells of the retina, particularly to photoreceptor cells, has broad potential both for answering basic questions of retinal biology and for more applied therapeutic purposes. The use of ribozymes as therapy for autosomal dominant retinal diseases is a promising technique, and the theoretical and practical basis for their use is discussed. The process involves designing and testing ribozymes first in vitro and then in animal models of retinal disease. Viral vectors based on the nonpathogenic human adeno-associated virus, when coupled with the strong, rod photoreceptor specific opsin promoter, offer an efficient and nontoxic way to deliver and express ribozymes in photoreceptor cells for long time periods of time. Effective ribozyme-mediated therapy also demands careful in vitro analysis of a ribozyme's ability to efficiently and specifically distinguish between mutant and wild type RNAs. Finally, effective demonstration of therapy in an animal model requires careful analysis of any rescue effect in the retina using multiple criteria, including biochemical, structural and physiological assays. For this purpose, ribozyme therapy in a transgenic rat model of retinitis pigmentosa containing a dominant rod opsin mutation (proline-to-histidine change at position 23) is discussed in detail.